The term "phospholipase A.sub.2 " (PLA.sub.2) refers to a large class of enzymes which cleave the sn-2 acyl group from phospholipids. The mammalian PLA.sub.2 enzymes involved in inflammatory reactions primarily release arachidonic acid from cell membrane phospholipids; this arachidonic acid is further converted into prostaglandins and leukotrienes. The action of PLA.sub.2 on 1-alkyl-2-acyl phospholipids leads to the production of platelet activating factor (PAF), another pro-inflammatory substance. An in vivo inhibitor of PLA.sub.2, therefore, would be expected to reduce the levels of prostaglandins, leukotrienes, and PAF in tissues. A drug with this activity may offer advantages over the presently known cyclooxygenase inhibitors (aspirin, indomethacin, and other NSAIDs), and also over lipoxygenase inhibitors and PAF antagonists, in the treatment of inflammatory conditions.
The corticosteroids (hydrocortisone and its many synthetic analogues) inhibit PLA.sub.2 indirectly, apparently by regulating the expression of a number of genes in mammalian cells, some of which code for PLA.sub.2 modulators. The resulting anti-inflammatory effect is far superior to that of the NSAIDs, but the many side-effects of steroids prevent their routine use in long-term treatment of chronic inflammatory diseases. A direct inhibitor of PLA.sub.2 would not affect gene expression, and would therefore be expected to exhibit steroid-like anti-inflammatory activity with fewer side-effects than the steroids.
A number of inhibitors of PLA.sub.2 have been described including manoalide which is a natural product with anti-inflammatory activity, produced by the marine sponge Luffariella variabilis. ##STR2##
The isolation and structure determination of manoalide were first reported by E. D. deSilva and P. J. Scheuer in Tetrahedron Letters, 21, 1611 (1980). Manoalide was subsequently reported to be a potent inhibitor of PLA.sub.2 by J. C. de Freitas et al., Experientia, 40, 864 (1984); this activity was also disclosed by R. S. Jacobs and D. J. Faulkner in U.S. Pat. No. 4,447,445. The latter patent also disclosed similar activities for seco-manoalide (a natural product) and dehydro-seco-manoalide (an artifact of isolation), which materials were first reported by de Silva and Scheuer in Tetrahedron Letters, 22, 3147 (1981). U.S. Pat. No. 5,037,811 discloses various furanone derivatives with anti-inflammatory activity.
It is an object of the present invention to provide novel 4-aryl or 4-arylthio-5-hydroxy-2(5H)-furanones which are useful as PLA.sub.2 inhibitors and antiinflammatory agents. As a class, 5-hydroxy-2(5H)-furanones have been known for some time, and a few 4-aryl derivatives are known. However, none of the known 4-aryl derivatives carry the RX group of the present invention, and the RX group is essential to the biological activity of the compounds of the invention.
It is an object of the present invention to provide novel methods of preparing the 4-aryl or 4-arylthio-5-hydroxy-2(5H)-furanones of the invention. Additional objects and advantages of the invention will be set forth, in part, in the description which follows and in part will be obvious from this description, or may be learned by practice of the invention. The objects and advantages of this invention are realized and obtained by means of the compositions, methods and the combinations particularly pointed out in the appended claims and their equivalents.